1. Field of the Invention
This invention resides in the field of cell surface molecules of mammalian cells, and particularly to ligands that bind to such molecules for purposes of inhibiting the biological activity of the cells, adhering a detectable label or imaging moiety to the cells, and of delivering therapeutic agents to the cells.
2. Description of the Prior Art
Receptors on the surfaces of mammalian cells take part in many biological processes that the cells perform, including cell invasion and cell proliferation. One particular receptor that has implications for a wide variety of disease conditions is the vitronectin receptor αvβ3 (which is also reported as αvβ3). This receptor is a member of the integrin superfamily of receptors and is associated with various cells including cells of the angiogenic endothelium and osteoclasts. As reported by Hood, J. D., et al., “Tumor Regression by Targeted Gene Delivery to the Neovasculature,” Science 296: 2404-2407 (28 Jun. 2002), αvβ3 plays a key role in endothelial cell survival during angiogenesis in vivo and potentiates the internalization of such viruses as foot-and-mouth disease virus, rotavirus, and adenovirus. By virtue of this potentiation, this receptor can be used to effect gene delivery by viral methods as well as other methods. Further useful qualities of the receptor are discussed by Duggan, M. E., et al., “Nonpeptide αvβ3 antagonists. 1. Transformation of a Potent, Integrin-Selective aIIIbβ3 Antagonist into a Potent avβ3 Antagonist,” J. Med. Chem. 43(20): 3736-3745 (2000), who report that αvβ3 is highly expressed in osteoclasts but not present in osteoblasts. This has led the authors to investigate use of the nonpeptide antagonists as pharmaceutical agents for the treatment of osteoporosis. Further discussion by the same authors is found in Hartmann, G. D., et al., U.S. Pat. No. 5,741,796, issued Apr. 21, 1998, which cites the administration of the same nonpeptide antagonists in the treatment of hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment. Other nonpeptide antagonists of vβ3 are reported in International Patent Application Publication No. WO 99/52879 (applicant: American Home Products Corporation, inventors: Kees, K. L., et al., international publication date: 21 Oct. 1999) and its United States counterpart, United States Pre-Grant Publication No. U.S. 2003 0186967 A1, Kees, K. L., et al., publication date 02 Oct. 2003. These Kees et al. publications report the activity of vβ3 in mediating the invasion of malignant melanoma cells into healthy tissue, in protecting cells against apoptosis, in mediating the growth of solid tumors, and in liver metastasis. Peptide antagonists have also been studied, notably antibodies to avβ3, as well as proteins that possess the three-amino acid sequence arginine-glycine-aspartic acid (RGD). Such proteins include echistatin, vitronectin, osteopontin, and bone sialoprotein. Non-peptide mimics of these proteins have also been studied.